Death or destruction of nervous tissue such as neurons or glial cells is associated with a variety of degenerative disorders of the nervous system. These disorders include, for example, degenerative diseases such as Alzheimer""s disease, Parkinson""s disease, Huntington""s chorea, and amyotrophic lateral sclerosis. Necrosis or loss of neurons is also associated with neuropathies of the central, peripheral or motor neurons as a result of disease states such as diabetes. In addition, damage to neurons may result from ischemia due to stroke, trauma (e.g. burns and wounds), kidney dysfunction as well as the toxic effects of drugs used to treat cancer and AIDS. Further, the loss of neurons may result in dementia associated with aging.
Currently, there are no known effective treatments for damaged or degenerated nervous tissue. Certain growth factors such as ciliary neurotrophic factor (CNTF) have been proposed for the treatment of neurodegenerative diseases such as Alzheimer""s disease. However, the use of CNTF has not been successful in clinical trials. Thus, there is a present need for the identification of new agents for treating damaged and degenerated nervous tissue.
Kothapalli, et al. described the identification of a novel human gene encoding endometrial bleeding associated factor protein (xe2x80x9cebafxe2x80x9d) that is associated with abnormal endometrial bleeding (J. Clin. Invest., 99(10):2342-50, 1997). The ebaf gene is located on human chromosome 1 at band q42.1, and the nucleotide and deduced amino acid sequences are known (Kothapalli, et al., 1997). The sequence of the ebaf protein also shows homology and structural features of the members of the TGF-xcex2 superfamily (Kothapalli, et al., 1997). The ebaf gene is expressed in human endometrium in the late secretory and menstrual phases and absent in the early and mid-secretory endometria (Tabibzadeh, et aL, Mol. Hum. Reprod, 4(6):595-602, 1998), and also in certain adenocarcinomas that exhibited mucinous differentiation including colonic, duodenal, and ovarian carcinomas (Tabibzadeh, et al., Front. Biosci., 15(2):18-25, 1997).
Meno, et al. have described two mouse members of the TGF-xcex2 superfamily, designated Lefty-1 and Lefty-2. These are expressed in a left-right asymmetric fashion in mouse embryos, and are separated by about 30 kb on mouse chromosome 1H2 (Meno, et al., Genes Cells, 2(8):513-24, 1997). Meno, et al. also reported that Lefty-1 induces NCAM-1 (a neural marker) in the absence of mesoderm induction, and hypothesized that the direct neutralizing activities of Lefty-1, similar to BMP antagonists such as noggin and chordin, may antagonize BMP (bone morphogenic protein)-mediated signals in tissues positioned on the left side of mouse embryos.
Recently, Kosaki, et al. described the identification of two human lefty genes, designated Lefty-A and Lefty-B, that are separated by approximately 50 kb on chromosome 1q42 (Am. J. Hum. Genet. 64(3):712-21, 1999). Lefty-A was described as being identical to ebaf. Although human Lefty-A and Lefty-B and mouse Lefty-1 and Lefty-2 are similar, Kosaki, et al. described that human Lefty-A and Lefty-B are more similar to each other than to mouse Lefty-1 and Lefty-2. In this regard, Kosaki, et al. described that Lefty-A and Lefty-B are 96% homologous and mouse Lefty-1 and Lefty-2 are 90% homologous, while the cross-species homology is only 81-82%. Thus, Kosaki, et al. suggested that sequence analysis alone precludes determination of specific orthologous relationships (i.e. whether Lefty-A is the functional equivalent of Lefty-1).
The present invention is based on the discovery that ebaf is associated with the development and growth of nervous tissue. Based on this finding, the present invention provides a method for inducing the growth or enhancing survival of nervous tissue comprising contacting the nervous tissue with an amount of ebaf effective to induce the growth or enhance the survival of the nervous tissue. The present invention also provides a method for treating a subject having damaged or degenerated nervous tissue comprising administering to the subject an amount of ebaf effective to treat the damaged or degenerated nervous tissue.
The present invention further provides a method for treating a neurodegenerative disease in a subject comprising administering an amount of ebaf effective to treat the neurodegenerative disease. The present invention still further provides a method for preventing the onset or reducing the severity of damaged or degenerated nervous tissue in a subject comprising administering an amount of ebaf effective to prevent the onset or reduce the severity of the damaged or degenerated nervous tissue.
Lastly, the present invention provides a method for inducing growth or enhancing survival of nervous tissue comprising contacting the nervous tissue with a modulator of ebaf expression in an amount effective to induce or enhance expression of ebaf and induce the growth or enhance the survival of the nervous tissue. Additional objects of the present invention will be apparent in view of the description which follows.